Wolfgang N. Löscher

Carpal Tunnel Syndrome Assessment with US: Value of Additional Cross-sectional Area Measurements of the Median Nerve in Patients versus Healthy Volunteers

PURPOSE To improve accuracy in the diagnosis of carpal tunnel syndrome (CTS) by comparing cross-sectional area (CSA) measurements of the median nerve obtained at the level of the carpal tunnel (CSAc) with those obtained more proximally (CSAp), at the level of the pronator quadratus muscle. MATERIALS AND METHODS The study protocol was approved by the institutional review board, and all subjects gave written informed consent. One hundred wrists of 68 consecutive patients with CTS (16 men, 52 women; mean age, 57.9 years; range, 25-85 years) and 93 wrists of 58 healthy volunteers (16 male, 42 female; mean age, 55.1 years; range, 17-85 years) were examined with ultrasonography (US). Electrodiagnostic test results confirmed the diagnosis of CTS in all 68 patients. The US examiner was blinded to these test results. The CSA of the median nerve was measured at the carpal tunnel and proximal levels, and the difference between CSAc and CSAp (Delta CSA) was calculated for each wrist. RESULTS The mean CSAc in healthy volunteers (9.0 mm(2)) was smaller than that in patients (16.8 mm(2), P < .01). The mean Delta CSA was smaller in asymptomatic wrists (0.25 mm(2)) than in CTS-affected wrists (7.4 mm(2), P < .01). Receiver operating characteristic analysis revealed a diagnostic advantage to using the Delta CSA rather than the CSAc (P = .036). Use of a Delta CSA threshold of 2 mm(2) yielded the greatest sensitivity (99%) and specificity (100%) for the diagnosis of CTS. CONCLUSION Receiver operating characteristic analysis revealed improved accuracy in the diagnosis of CTS determined with the Delta CSA compared with the accuracy of the diagnosis determined with the CSAc.

Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance

Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic.

An X-Linked Myopathy with Postural Muscle Atrophy and Generalized Hypertrophy, Termed XMPMA, Is Caused by Mutations in FHL1

We have identified a large multigenerational Austrian family displaying a novel form of X-linked recessive myopathy. Affected individuals develop an adult-onset scapulo-axio-peroneal myopathy with bent-spine syndrome characterized by specific atrophy of postural muscles along with pseudoathleticism or hypertrophy and cardiac involvement. Known X-linked myopathies were excluded by simple-tandem-repeat polymorphism (STRP) and single-nucleotide polymorphism (SNP) analysis, direct gene sequencing, and immunohistochemical analysis. STRP analysis revealed significant linkage at Xq25-q27.1. Haplotype analysis based on SNP microarray data from selected family members confirmed this linkage region on the distal arm of the X chromosome, thereby narrowing down the critical interval to 12 Mb. Sequencing of functional candidate genes led to the identification of a missense mutation within the four and a half LIM domain 1 gene (FHL1), which putatively disrupts the fourth LIM domain of the protein. Mutation screening of FHL1 in a myopathy family from the UK exhibiting an almost identical phenotype revealed a 3 bp insertion mutation within the second LIM domain. FHL1 on Xq26.3 is highly expressed in skeletal and cardiac muscles. Western-blot analysis of muscle biopsies showed a marked decrease in protein expression of FHL1 in patients, in concordance with the genetic data. In summary, we have to our knowledge characterized a new disorder, X-linked myopathy with postural muscle atrophy (XMPMA), and identified FHL1 as the causative gene. This is the first FHL protein to be identified in conjunction with a human genetic disorder and further supports the role of FHL proteins in the development and maintenance of muscle tissue. Mutation screening of FHL1 should be considered for patients with uncharacterized myopathies and cardiomyopathies.

Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.

Significance of peripheral afferent input to the α-motoneurone pool for enhancement of tremor during an isometric fatiguing contraction

Abstract The objective of this study was to investigate the contribution of peripheral afferent input to the enhancement of isometric tremor during a sustained submaximal isometric contraction. It was hypothesised that during muscle fatigue, when excitatory drive is high, peripheral afferent input may augment oscillations in the stretch reflex arc and result in bursting motor-unit activity and increased tremor. Nine healthy subjects maintained isometric plantar flexions at 30% of their maximum voluntary contraction until the limit of endurance, under three test conditions. Two paradigms were used to reduce afferent input to the triceps surae α-motoneurone pool: (1) continued vibration of the Achilles tendon, and (2) ischaemic partial block of the tibial nerve. These were compared to a control experiment, in which there was no intervention. By recording H-reflexes from the gastrocnemius and soleus muscles, it was possible to assess the effectiveness of reducing the afferent input. When H-reflex suppression had stabilised, the fatiguing contraction was commenced and tremor was computed from the continuously recorded torque signal. Superimposed maximum twitches were elicited as indirect measures of excitatory drive. The increase in tremor root mean square throughout the fatiguing contraction was significantly less for both the vibration and ischaemic conditions. Furthermore, tremor mean power frequency decreased significantly with endurance time in the control experiment, while no significant change was seen in the other two experimental conditions. It is concluded that the enhancement of isometric tremor seen during a fatiguing submaximal isometric contraction is facilitated by peripheral afferent input to the α-motoneurone pool.

Central fatigue and motor cortical excitability during repeated shortening and lengthening actions

A decline in voluntary muscle activation and adaptations in motor cortical excitability contribute to the progressive decline in voluntary force during sustained isometric contractions. However, the neuronal control of muscle activation differs between isometric and dynamic contractions. This study was designed to investigate voluntary activation, motor cortex excitability, and intracortical inhibition during fatiguing concentric and eccentric actions. Eight subjects performed 143 torque motor–controlled, repeated shortening and lengthening actions of the elbow flexor muscles. Transcranial magnetic stimulation (TMS) was applied three times every 20 cycles. Magnetic evoked motor potentials (MEP), duration of the silent period (SP), and the torque increase due to TMS were analyzed. TMS resulted in a small torque increase in unfatigued actions. With repeated actions, voluntary torque dropped rapidly and the amplitude of the TMS‐induced twitches increased, especially during repeated lengthening actions. MEP area of biceps brachii and brachioradialis muscles increased during repeated actions to a similar extent during lengthening and shortening fatigue. The duration of biceps and brachioradialis SP did not change with fatigue. Thus, voluntary activation became suboptimal during fatiguing dynamic actions and motor cortex excitability increased without any changes in intracortical inhibition. The apparent dissociation of voluntary activation and motor cortex excitability suggests that the central fatigue observed, especially during lengthening actions, did not result from changes in motor cortex excitability.

Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia.

Inherited peripheral neuropathies are frequent neuromuscular disorders known for their clinical and genetic heterogeneity. In 33 families, we identified 8 mutations in HINT1 (encoding histidine triad nucleotide–binding protein 1) by combining linkage analyses with next-generation sequencing and subsequent cohort screening of affected individuals. Our study provides evidence that loss of functional HINT1 protein results in a distinct phenotype of autosomal recessive axonal neuropathy with neuromyotonia.

Comparison of second lumbrical and interosseus latencies with standard measures of median nerve function across the carpal tunnel: a prospective study of 450 hands

Abstract The second lumbrical-interosseus distal motor latency (2LI-DML) was compared prospectively in 450 hands. Median nerve function was assessed by standard motor and sensory electrophysiological tests. In a control group of 100 hands the upper limit of normal for the 2LI-DML was 0.5 ms. In all hands studied the correlation coefficients of 2LI-DML were higher with sensory nerve tests than with motor studies. Carpal tunnel syndrome (CTS) was diagnosed clinically in 276 hands, and 174 showed no clinical signs of CTS. The 2LI-DML was prolonged in 269 of the 276 hands, with clinical signs of CTS and normal in 170 of 174 non-CTS hands. Thus the 2LI-DML resulted in a sensitivity of 97.5 %. On the other hand, combining the standard tests yielded a sensitivity of 98.5 %. In 31 of 36 additional hands a lumbrical response was recorded, although motor and sensory responses form standard median nerve conduction studies were absent, and the 2LI-DML was substantially prolonged. The 2LI-DML therefore represents a highly sensitive, fast, easy-to-perform, and cost-efficient method to study median nerve function across the wrist and may help to localize the lesion in cases in which standard electrophysiological methods fail.

Bifid Median Nerve in Carpal Tunnel Syndrome: Assessment with US Cross-sectional Area Measurement

PURPOSE To evaluate the accuracy of ultrasonography (US) in the diagnosis of carpal tunnel syndrome (CTS) in patients with a bifid median nerve on the basis of cross-sectional area (CSA) measurements of the median nerve at the level of the carpal tunnel (CSAc), with additional measurements obtained more proximally (CSAp) at the level of the pronator quadratus muscle. MATERIALS AND METHODS This HIPAA-compliant study was approved by the local institutional review board; informed oral and written consent were obtained. Fifty-three wrists in 49 consecutive patients with a bifid median nerve and CTS symptoms and 28 wrists in 27 healthy volunteers with a bifid median nerve were examined by using US. Two independent US examiners who were blinded to prior test results measured median nerve CSA at two levels, CSAc and CSAp. The difference between CSAc and CSAp (ΔCSA) was calculated for each wrist. Receiver operating characteristic (ROC) analysis was performed. RESULTS The study population included 17 men and 32 women (mean age, 55.1 years; age range, 24-78 years). The control population included 13 men and 14 women (mean age, 52.6 years; age range, 24-86 years). Mean CSAc was approximately 5 mm(2) greater in patients with CTS than in healthy volunteers (P < .0001), while mean ΔCSA was 5.8-5.9 mm(2) greater in patients with CTS (P < .0001). A CSAc threshold of 12 mm(2) provided sensitivity and specificity of 84.9% and 46.5%, respectively, while a ΔCSA threshold of 4 mm(2) provided sensitivity and specificity of 92.5% and 94.6%, respectively. ROC analysis demonstrated a significant advantage of ΔCSA (area under ROC curve [A(z)] = 0.95-0.96) compared with CSAc (A(z) = 0.84-0.85) for the diagnosis of CTS (P < .003). CONCLUSION The use of a ΔCSA parameter improves the diagnostic accuracy of US for the presence of CTS in patients with a bifid median nerve.

Load-dependence of fatigue related changes in tremor around 10 Hz

OBJECTIVES The aim of the study was to investigate the effects of different loads on tremor around 10 Hz during fatiguing contractions. METHODS Eighteen healthy volunteers performed sustained isometric knee extensions at 30%, 50% and 70% maximum voluntary contraction (MVC). During the fatiguing contractions, mechanical recordings were made with a high-resolution force sensor. Tremor-power was calculated for the 6-20 Hz frequency window as a function of time normalized to endurance time. RESULTS Initial tremor power was different between the high and low load tasks. Changes of tremor with contraction time differed between the three tasks, in that tremor of the 30% MVC contraction showed the least decrease throughout the sustained contraction, whilst that of the 50% and 70% MVC showed progressively higher decreases. At failure, all 3 contractions merged to the same tremor level. CONCLUSION Load-dependent, fatigue-related 6-20 Hz tremor changes during sustained submaximum voluntary contractions seem mainly the consequence of recruitment of new units and fatigue-related properties of the high threshold motor units of muscles.